Dendrimers are large, branched molecules which are members of a versatile, fourth class of polymer architecture (i.e. dendritic polymers after traditional linear, cross-linked and branched types) (Tomalia 2002). Typically, dendrimers have well-defined scaffolding and are conjugated to, complexed with or used to encapsulate therapeutic drugs or imaging moieties (Menjoge 2010, Röglin 2011).
Dendrimers have properties that are of interest to the pharmaceutical industry, particularly their size and multi-valency. For example, US2009/0036353 A1 relates to insulin conjugated with structurally well-defined dendrimers which have glycerol units at the branching points. Zanini and Roy (Zanini 1996) describe the design and synthesis of symmetrical glycodendrimers with even valencies from 2 to 16, which are built on glycine as the branching point and which end with equidistant thiosialoside residues. The synthetic strategy employed allowed for the incorporation of different carbohydrate haptens into the prebuilt dendritic structures. The branched molecules described by Negm and Hafiz (Negm 2004, 2005; Hafiz 2005) have charged quaternary tetra-alkylated nitrogens within the structure and can be used as antimicrobial agents and for nucleic acid delivery into cells.
The above examples focus on the use of dendrimers as drug delivery vehicles or diagnostic tools. However, dendrimers may also be used as drugs in their own right. For example, the dendrimer SPL7013 is a vaginal microbicide (McCarthy 2005) which has been developed to prevent the transmission of sexually transmitted infections and to treat bacterial vaginosis.
The encapsulation of imaging agents and therapeutic agents into dendrimer compounds has also been the subject of increasing research. Morgan (2006) showed that the anti-cancer drug camptothecin could be encapsulated in a biocompatible polyester dendrimer and Boisselier (2010) shows that vitamins could be encapsulated in both di-aminobutane (DAB) and PAMAM dendrimers. Polypropyleneimines (PPI dendrimers) functionalised by glycerol-based entities have also been examined for the encapsulation of MRI contrast reagents to improve relaxivitiy times (Balieu 2012).
A recent review on dendrimer based products (Menjoge 2010) demonstrates the applicability of dendrimers in a commercial setting. Dendrimers have been successfully used in the commercial market for diagnostics, for example the SuperFect transfection reagent marketed by Qiagen that utilises a PAMAM dendrimer.
In the pharmaceutical and imaging arena, however, only a few products have entered into clinical trials, most notably Starpharma's VivaGel™ and Schering-Plough's Gadomer-17 MRI contrast agent that both contain poly-lysine dendrimeric cores. For dendrimers to be of use as therapeutic drugs, they must have low toxicity with a suitable, known safe dosing window; high stability with measurable degradation, producing degradants of low toxicity; low cost of goods and to be able to be made by an efficient, scalable synthesis; high, HPLC measurable purity; suitable solubility in biologically relevant media; and must have amine or carboxylic acid termini available for further modification by subsequent capping reactions. This is a challenging set of criteria that most existing dendrimer constructs fail.
It is therefore the object of this invention to provide novel dendrimer compounds that adequately address the above criteria and in particular, elaborated dendrimer compounds to which active and/or inactive agent(s) can be attached to, and/or encapsulated within.